FASEB journal : official publication of the Federation of American Societies for Experimental BiologyNov 13, 2025

Lack of HMGB2 in Bone Marrow Stem Cells May Promote Age-Related Bone Loss by Blocking Bone-Building Cell Development Through Inflammation

Regenerative Health Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

HMGB2 overexpression reverses senescence-mediated osteogenic impairment in bone marrow mesenchymal stem cells.

Cellular senescence is associated with reduced osteogenic differentiation and proliferation of bone marrow mesenchymal stem cells.
In vivo studies show a strong correlation between decreased HMGB2 levels and the progression of osteoporosis in aging mice.
HMGB2 promotes bone formation by inhibiting the inflammatory cytokine TNF-α and stabilizing the long non-coding RNA TUG1.
The stabilization of TUG1 by HMGB2 leads to the suppression of pro-inflammatory cytokines IL-1β and IL-6.
This study identifies a novel regulatory axis involving HMGB2 and TUG1 that may influence stem cell differentiation.

Simplified

With the global rise in osteoporosis due to aging, impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) has emerged as a critical pathogenic factor. Although high mobility group box 2 (HMGB2) is implicated in BMSC aging and organismal senescence, its mechanistic role in osteoporosis remains unclear. Here, we investigate HMGB2's regulatory effects on BMSC osteogenic differentiation under aging conditions. Using an HO-induced BMSC senescence model, we demonstrate that cellular senescence suppresses osteogenic differentiation, evidenced by reduced expression of osteogenic markers and diminished proliferation. Notably, HMGB2 overexpression reversed senescence-mediated osteogenic impairment. In vivo studies of ovariectomy-induced aging mice revealed a strong correlation between HMGB2 downregulation and osteoporosis progression, confirmed via immunohistochemistry. Mechanistically, HMGB2 promotes osteogenesis by directly suppressing TNF-α and stabilizing the long non-coding RNA TUG1, which subsequently inhibits pro-inflammatory cytokines IL-1β and IL-6. This dual regulatory pathway highlights HMGB2's role in counteracting senescence-driven osteogenic decline. Our study not only elucidates a novel HMGB2/TUG1 axis governing stem cell differentiation but also identifies HMGB2 as a promising therapeutic target for combating osteoporosis. 2 2

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Lack of HMGB2 in Bone Marrow Stem Cells May Promote Age-Related Bone Loss by Blocking Bone-Building Cell Development Through Inflammation

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